Our results in the preceding funding period lead us to propose that immunodominance in CD4 T cell responses is largely dictated by an intrinsic property of the peptide:class II complex, which is measured by its kinetic stability. This single parameter can be rationally and experimentally manipulated to either promote or eliminate immune responses. Mechanistically, we have determined that DM editing in APC is a key event that is altered by the kinetic stability of class II:peptide complexes. Accordingly high stability complexes will be expressed at the cell surface of the priming APC at much greater initial densities than other, competing low stability peptides. In this renewal application, using the tools and knowledge of peptide:MHC class II interactions that we have developed, we will shift our attention from the role of antigen processing in determining immunodominance to the dynamic and kinetic aspects of APC-T cell interactions in establishing peptide hierarchies in CD4 T cell responses. We will critically test whether the initial epitope density is the sole element that programs immunodominance hierarchies. We hypothesize that the kinetic stability of peptide:class II complexes may play additional roles in CD4 T cell priming, independent of DM effects and that T cell hierarchies may be re-shaped over time and by ongoing simultaneous responses to different peptides within the protein antigen. Below are our experimental plans to address these issues.
Specific Aim 1 : Determine when and through what mechanisms immunodominance hierarchies in CD4 T cell responses are initiated and maintained Specific Aim 2. Determine the impact of simultaneous, competing CD4 T cell responses to unrelated peptides in shaping immunodominance. These will provide a new and significant view of the kinetics of acquisition and maintenance of the antigen-specific repertoire and competitive nature of T cell activation, expansion and contraction that are regulated by T cell receptor engagement. The insight gained from these clarify the studies will help provide insight into the factors that shape the specificity in CD4 T cell responses to pathogens and will have significant impact in the design of vaccines that seek to either focus or alternatively to diversify the specificity of CD4 T cell responses. Public Health Relevance: In the previous funding period, we discovered a single critical factor that determines what segments in the pathogen or vaccines are selected be the focus of the immune response. In the experiments planned, we will determine how this single variable focuses the immune response towards such limited regions of the e pathogen. The results of these experiments will help in the design of vaccines that focus or diversify the immune response to pathogenic organisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051542-10
Application #
8293350
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2002-09-30
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$377,339
Indirect Cost
$132,314
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Richards, Katherine A; Nayak, Jennifer; Chaves, Francisco A et al. (2015) Seasonal Influenza Can Poise Hosts for CD4 T-Cell Immunity to H7N9 Avian Influenza. J Infect Dis 212:86-94
Alam, Shabnam; Knowlden, Zackery A G; Sangster, Mark Y et al. (2014) CD4 T cell help is limiting and selective during the primary B cell response to influenza virus infection. J Virol 88:314-24
Sant, Andrea J; Chaves, Francisco A; Leddon, Scott A et al. (2013) The control of the specificity of CD4 T cell responses: thresholds, breakpoints, and ceilings. Front Immunol 4:340
Tung, Jacqueline; Sant, Andrea J (2013) Orchestration of CD4 T cell epitope preferences after multipeptide immunization. J Immunol 191:764-72
Richards, Katherine A; Chaves, Francisco A; Alam, Shabnam et al. (2012) Trivalent inactivated influenza vaccines induce broad immunological reactivity to both internal virion components and influenza surface proteins. Vaccine 31:219-25
Leddon, Scott A; Sant, Andrea J (2012) The peptide specificity of the endogenous T follicular helper cell repertoire generated after protein immunization. PLoS One 7:e46952
Chaves, Francisco A; Lee, Alvin H; Nayak, Jennifer L et al. (2012) The utility and limitations of current Web-available algorithms to predict peptides recognized by CD4 T cells in response to pathogen infection. J Immunol 188:4235-48
Nayak, Jennifer L; Sant, Andrea J (2012) Loss in CD4 T-cell responses to multiple epitopes in influenza due to expression of one additional MHC class II molecule in the host. Immunology 136:425-36
Alam, Shabnam; Sant, Andrea J (2011) Infection with seasonal influenza virus elicits CD4 T cells specific for genetically conserved epitopes that can be rapidly mobilized for protective immunity to pandemic H1N1 influenza virus. J Virol 85:13310-21
Richards, Katherine A; Chaves, Francisco A; Sant, Andrea J (2011) The memory phase of the CD4 T-cell response to influenza virus infection maintains its diverse antigen specificity. Immunology 133:246-56

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